Conceptualized model of PAM modulation directly on TRPV1. Homotetrameric TRPV1 is permeable to cations, notably sodium and calcium, and possesses an orthosteric binding site for capsaicin and an allosteric binding site. At baseline, no agonist is bound and the channel is closed (far left). Binding of a positive allosteric modulator does not activate channel opening (mid left). When an agonist such as capsaicin binds (mid right), a conformational change allows sodium and calcium to flow into the neuron resulting in depolarization and, if threshold is reached, generation of an action potential. When capsaicin binds, the allosteric site targeted by a PAM (far right) then becomes functionally accessible. The PAM increases cation influx and the likelihood of axonal depolarization. Sufficient depolarization can result in calcium-induced cytotoxicity leading to inactivation of the conductive potential of the axon and analgesia.